River Plume Liftoff Dynamics and Surface Expressions.

The water surface expression of liftoff and its dependence on discharge are examined using numerical simulations with the Regional Ocean Modeling System (ROMS). Liftoff is the process by which buoyant river water separates from the bed and flows over denser saltwater. During low-discharge conditions liftoff occurs in the river and is accompanied by a change in the surface slope. During high-discharge conditions liftoff occurs outside the mouth and generates a ridge on the water surface. The location and height of the ridge can be described by analytical equations in terms of discharge, shelf slope, and river mouth aspect ratio. The offshore distance and height of the ridge are proportional to the river discharge and vary inversely with river mouth aspect ratio. For steep shelf slopes liftoff occurs close to the river mouth and generates a large ridge. The ridge is modified, but not eliminated, by the presence of tides. The water surface slope change at the ridge peak is large enough to be detected by the upcoming Surface Water and Ocean Topography (SWOT) altimeter and can be used to identify the liftoff location during high discharge. However, during low discharge the water surface slope change at the liftoff location is too small to be detected by SWOT. These results indicate that remote measurements of the presence or absence of the ridge may be useful to distinguish between low and high flows, and remote measurements of the ridge location or height could be used to estimate freshwater discharge.

Indomethacin is a placental vasodilator in the dog. The effect of prostaglandin inhibition.

The effect of 8 mg/kg of indomethacin on uterine blood flow, prostaglandin production, and intraamniotic fluid pressure was examined in late pregnant dogs. Uterine blood flow was measured with 15 mum radiolabeled microspheres. Because we found that a significant percentage of the microspheres shunted through the placental circulation into the lungs, we calculated placental blood flow by adding the shunted microspheres through the placenta to the nonshunted microspheres in the placenta. Total uterine blood flow significantly increased from 271+/-69 ml/min during control period to 371+/-72 ml/min (P < 0.01) 30 min after indomethacin. This increase was attributable to the change in blood flow to the placental circulation (222+/-58 to 325+/-63 ml/min; P < 0.01). Associated with these hemodynamic changes we found an almost complete suppression of uterine prostaglandin E(2) production (1,654+/-305 to 51+/-25 pg/ml; P < 0.01) as measured by gas chromatography-mass spectrometry. In addition, we found that indomethacin treatment resulted in uterine relaxation as measured by intraamniotic fluid pressure changes (11.2+/-1.3 mm Hg to 8.5+/-1.2 mm Hg; P < 0.001). We conclude that indomethacin causes an increase in placental blood flow without any change in flow to the rest of the uterus, and that this dose of the drug inhibits greater than 95% of uterine prostaglandin production. In addition, indomethacin is responsible for uterine relaxation. The increase in placental blood flow after indomethacin is probably a result of uterine relaxation, which is secondary to prostaglandin synthesis inhibition.

Increased clearance of antipyrine and d-propranolol after phenobarbital treatment in the monkey. Relative contributions of enzyme induction and increased hepatic blood flow.

The effects of phenobarbital treatment for 12 days on the regional distribution of blood flow and on the disposition of two model drugs, antipyrine and d-propranolol, have been determined in six unanesthetized rhesus monkeys. Phenobarbital significantly increased total hepatic blood flow from 179+/-15 to 239+/-27 ml/min. Liver weight was increased to a similar degree (34%) in phenobarbital-treated animals as compared to control monkeys. The clearance of both antipyrine and d-propranolol was increased and the half-life decreased significantly by phenobarbital. Analysis of the data by a perfusion-limited pharmacokinetic model showed that the changes in antipyrine clearance were due almost entirely to enzyme induction. On the other hand, with d-propranolol, the increase in liver blood flow contributed as much to the enhanced clearance as did the stimulation of drug metabolism. The mechanism by which phenobarbital produces the frequently observed increase in drug clearance, therefore, depends upon the initial clearance value of the drug. For low clearance drugs like antipyrine, clearance changes occur largely as a result of enzyme induction. With higher clearance drugs, the effects of increased hepatic blood flow become progressively more important the greater the initial clearance value.

Caffeine enhances the slow-pressor response to angiotensin II in rats. Evidence for a caffeine-angiotensin II interaction with the sympathetic nervous system.

The purpose of this study was to determine if caffeine augments the slow-pressor response to chronic low-dose infusions of angiotensin II (AII) or the rapid-pressor response to acute infusions of AII. AII was infused (125 ng/min i.p.) for 12 d via mini-osmotic pumps in four groups of rats: group I, intact rats not treated with caffeine (n = 9); group II, intact rats treated with caffeine (0.1% in drinking water, n = 9); group III, rats previously sympathectomized with 6-hydroxydopamine, but not treated with caffeine (n = 10); and group IV, rats previously sympathectomized with 6-hydroxydopamine and treated with caffeine (n = 10). Chronic low-dose AII infusions slowly elevated systolic blood pressure in all groups. Caffeine greatly augmented this slow-pressor response to AII in intact animals; however, caffeine failed to enhance AII-induced hypertension in sympathectomized rats. Caffeine pretreatment did not enhance the rapid-pressor response to acute intravenous infusions of AII. We conclude that caffeine augmented the slow-pressor effect of chronic low-dose infusions of AII via a mechanism that involved the sympathetic nervous system.

Chronic caffeine administration exacerbates renovascular, but not genetic, hypertension in rats.

The purpose of this study was to determine whether or not caffeine would exacerbate renovascular hypertension. Therefore, we examined the effects of chronic caffeine administration on arterial blood pressure in rats subjected to either unilateral renal artery clipping (2K-1C rats) or sham-operation. Animals in each group were randomly assigned to receive either 0.1% caffeine in their drinking water or normal drinking water, and systolic blood pressure was monitored for 6 wk. Caffeine markedly exacerbated the severity of hypertension in 2K-1C rats and caused histological changes consistent with malignant hypertension. 6 wk after surgery, systolic blood pressure, plasma renin activity, and creatinine clearance in control 2K-1C rats were 169 +/- 5 mmHg (mean +/- SEM), 4.4 +/- 0.5 ng AI X ml-1 X h-1, and 2.9 +/- 0.2 ml/min, respectively; as compared with 219 +/- 4 mmHg, 31.8 +/- 7.8 ng AI X ml-1 X h-1, and 1.4 +/- 0.3 ml/min, respectively, in 2K-1C rats receiving caffeine (all values were significantly different compared with control 2K-1C). Chronic caffeine administration did not alter systolic blood pressure, plasma renin activity, or creatinine clearance in sham-operated rats or spontaneously hypertensive rats. Chronic treatment with enalapril (a converting enzyme inhibitor) prevented the development of hypertension in control 2K-1C rats and caffeine-treated 2K-1C rats; however, withdrawal of enalapril precipitated a rapid rise in systolic blood pressure in caffeine-treated 2K-1C rats, but not in control 2K-1C rats. These experiments indicate that caffeine specifically exacerbates experimental renovascular hypertension and might worsen the hypertensive process in patients with renovascular hypertension.

Genetic predisposition to bladder cancer: ability to hydroxylate debrisoquine and mephenytoin as risk factors.

The hypothesis that the frequency distribution of indices of oxidative drug-metabolizing activity is different between patients with bladder cancer (n = 98) and age, sex-matched control subjects (n = 110) has been investigated. Urinary recovery ratios of debrisoquine and R/S ratios of mephenytoin have been measured in an 8-h urine sample after simultaneous administration of debrisoquine (10 mg) and racemic mephenytoin (100 mg). In addition, alcohol consumption, smoking habit, and acetylation phenotype (using 100 mg dapsone as a substrate) have been measured. Patients with bladder cancer were classified on histological criteria as having aggressive (Stage III) (34%) or nonaggressive (Stages I and II) (66%) disease. The median of the frequency distribution of the debrisoquine urinary recovery ratio in patients with aggressive bladder cancer was greater than in control subjects, and only four patients had recovery ratios lower than the mean of the control group. Using logistic regression analysis, efficient debrisoquine metabolism and a synergistic interaction between smoking and ethanol consumption were significant, independent risk factors, while S-mephenytoin hydroxylation and acetylation phenotype were not significant risk factors. In contrast, patients with non-aggressive bladder cancer had a significant, but weaker, association with rapid hydroxylation of S-mephenytoin, which was independent of a significant synergistic interaction between smoking and alcohol consumption. Acetylation phenotype and debrisoquine urinary recovery ratio were not associated with increased risk of nonaggressive cancer. These results are consistent with the concept that oxidative isozymes might be responsible for conversion of environmental agents to proximate bladder carcinogens in nonindustrial-related bladder cancer. They also suggest that different etiological factors are involved in the pathogenesis of aggressive and nonaggressive bladder cancer.

Duloxetine pharmacokinetics in cirrhotics compared with healthy subjects.

OBJECTIVE: To compare the pharmacokinetics of single-dose duloxetine in cirrhotic and healthy subjects. METHODS: An open-label inpatient study compared duloxetine pharmacokinetics in six subjects with moderate liver cirrhosis (Child-Pugh class B) to those in six healthy subjects. Subjects received a single 20 mg capsule of duloxetine following overnight fasting. Blood samples were collected up to 120 h post dose for determination of plasma concentrations of duloxetine and its major metabolites using a validated LC/MS/MS method. Plasma concentration-time data for duloxetine and its major metabolites were analyzed by noncompartmental methods. Specific pharmacokinetic parameters were assessed statistically using a mixed-effects model. RESULTS: Duloxetine apparent clearance was significantly lower (24 vs 160 l/h, p < 0.05) and AUC values were substantially higher (775 vs 268 ng x (h/ml) in cirrhotic compared to healthy subjects. The half-life of duloxetine was about three times longer (47.8 vs 13.5 h) in cirrhotic than in healthy subjects (p < 0.05). In contrast, there was no significant difference in Cmax or apparent volume of distribution between the two groups. The metabolites exhibited lower levels and longer half-lives in cirrhotic subjects compared to healthy subjects. The lower clearance and slower elimination of duloxetine in cirrhotic individuals is likely attributable to impaired duloxetine metabolism. CONCLUSIONS: The rate of duloxetine elimination is reduced for cirrhotic subjects, making dosage adjustments appropriate. Based on simulations, the duloxetine dose for at least an initial treatment period may need to be reduced and/or less frequently administered for patients with moderate cirrhosis.

Prevention of amphotericin B-induced renal impairment. A review on the use of sodium supplementation.

Amphotericin B is the treatment of choice for most deep-seated mycoses; however, doses may have to be limited because of concern over adverse effects such as nephrotoxicity. Evolving evidence suggests that the extent of amphotericin B-induced renal impairment may be modified via alteration of a normal physiologic feedback response that further contributes to changes due to direct nephrotoxicity. As such, renal impairment has a substantial theoretically preventable and reversible element. In animals exposed to amphotericin B, sodium loading interferes with this response. Mounting clinical evidence also supports the usefulness of sodium supplementation to prevent as well as to reverse amphotericin B-induced nephrotoxicity. At this time, the use of sodium supplementation (eg, intravenous saline and/or ticarcillin disodium, which contains 5.2 mEq of sodium per gram of drug) along with avoiding dehydration appears to be a safe and effective means of reducing the risk of nephrotoxicity associated with amphotericin B administration; however, it is not known whether renal changes can be entirely prevented. These preliminary observations merit confirmation in a prospective, randomized clinical trial.

Hemodynamic effects of adenosine in conscious hypertensive and normotensive rats.

Mean arterial pressure and heart rate were measured during intra-aortic arch (i.a.a.), intravenous, and suprarenal artery (s.r.a.) infusions of adenosine in conscious, unrestrained normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) in the absence and presence of ganglionic blockade. In both groups, i.a.a. and i.v. infusions of adenosine induced comparatively larger dose-dependent reductions in mean arterial pressure than did s.r.a. infusions. In WKY, i.a.a. and i.v. infusions of adenosine were equipotent in reducing mean arterial pressure. In contrast, i.a.a. infusion of adenosine was approximately twice as potent as i.v. infusion in SHR. Also, SHR were approximately 6.5 and 2.6 times more sensitive to i.a.a. and i.v. infusions of adenosine, respectively, than were WKY. Further, i.a.a. and s.r.a. infusions of adenosine caused tachycardia in WKY, while i.v. infusions did not alter heart rate. In SHR, neither i.a.a. nor s.r.a. infusion of adenosine altered heart rate, but i.v. infusion induced a profound bradycardia. In ganglionic-blocked WKY that received a norepinephrine infusion to restore blood pressure and heart rate to pre-ganglionic blockade levels, depressor responses to i.a.a. infusion of adenosine were unchanged while the increase in heart rate was abolished. In SHR, ganglionic blockade markedly decreased the depressor response to i.a.a. and i.v. infusions of adenosine and abolished the bradycardic response to i.v. infusion. These results suggest that adenosine is an effective hypotensive agent in both WKY and SHR; however, marked between-strain differences exist in the cardiovascular response to adenosine. These differences most likely are due to changes in adenosine-pulmonary interactions and increases in the importance of adenosine-autonomic interactions in SHR.

Adenosine in renin-dependent renovascular hypertension.

Our previous studies support the hypothesis that activation of the renin-angiotensin system by renal ischemia elevates adenosine levels and that adenosine acts in a negative feedback loop to limit renin release and to mitigate some of the hypertension-producing effects of angiotensin II. To further test this hypothesis, we compared the time course of caffeine-induced increases in plasma renin activity with the time course of changes in plasma levels of adenosine in two models of renin-dependent renovascular hypertension. Also, we compared the effects of caffeine on plasma renin activity and arterial blood pressure in renin-dependent versus renin-independent renovascular hypertension. In comparison to sham-operated rats, plasma levels of adenosine in the left and right renal veins and aorta were elevated severalfold in two-kidney, one clip rats (2K1C) 1 week after left renal artery clipping. However, adenosine levels declined during the second and third weeks after clipping. In 2K1C rats treated chronically with caffeine, plasma renin activity was markedly elevated during the first week after operation as compared to non-caffeine-treated 2K1C rats. However, during the second and third weeks after clipping, caffeine had lesser effects on plasma renin activity. A temporal relationship between plasma adenosine levels and caffeine-induced hyperreninemia was also observed in rats with aortic ligation. Caffeine accelerated hypertension in 2K1C rats and rats with aortic ligation (renin-dependent renovascular hypertension), but it had no effect on plasma renin activity or blood pressure in one-kidney, one clip rats (renin-independent renovascular hypertension). These results lend further support to the hypothesis that adenosine functions to mitigate the renin-angiotensin system in renin-dependent renovascular hypertension.

Effects of atrial natriuretic factor on hormone-induced renin release.

The purpose of this study was to determine whether or not atrial natriuretic factor can act directly on the juxtaglomerular cell in vivo to inhibit hormone-induced renin release. To achieve this objective the interaction between synthetic atrial natriuretic factor and two different renin secretagogues was examined. To exclude any indirect effect of atrial natriuretic factor on renin release due to changes in sodium delivery to the macula densa, all studies were conducted in nonfiltering, canine kidneys. In one series of studies renin release was stimulated by intrarenal infusions of norepinephrine (3 micrograms/kg/min), and in a second series of studies renin release was induced by intrarenal infusions of prostacyclin (0.1 micrograms/kg/min). In both studies intrarenal infusions of atrial natriuretic factor (0.3 micrograms/kg/min), which provided supraphysiological levels of atrial natriuretic factor in the renal arterial plasma, failed to attenuate hormone-induced renin release. In contrast, adenosine, a well-known inhibitor of renin release, abolished the renin release response to both hormones. These data indicate that, at the dose used in this study, synthetic atrial natriuretic factor does not act directly on the juxtaglomerular cell to attenuate hormone-induced renin release. Further, these results imply that circulating endogenous atrial natriuretic factor cannot directly attenuate juxtaglomerular cell responsiveness.

Endogenous prostacyclin synthesis is decreased during activation of the renin-angiotensin system in man.

Prostacyclin has been implicated as a mediator of renin release, whereas angiotensin II evokes prostaglandin I2 (PGI2) release from both vascular and nonvascular tissues in vitro. The physiological significance of these observations was assessed by measurement of an index of endogenous prostacyclin biosynthesis in human volunteers during varied activation of the renin-angiotensin system secondary to manipulation of dietary sodium. Excretion of the major urinary metabolite of prostacyclin in man, 2,3-dinor-6-keto-PGF1 alpha (PGI-M), fell from 295 +/- 51 to 176 +/- 35 (+/- SEM) ng g creatinine-1 (P less than 0.01) in 10 normal subjects when sodium intake was decreased from 150 to 10 meq/day. In five patients with primary hyperaldosteronism, PGI-M fell from 199 +/- 34 ng g creatinine-1 preoperatively to 120 +/- 26 pg/mg creatinine-1 after removal of the adenoma. In such patients, the reduction in PGI-M was associated with a significant increase in PRA. Thus, in both normal subjects and patients with hyperaldosteronism, PGI-M excretion fell rather than increased with activation of the renin-angiotensin system. This suggests that systemic biosynthesis of PGI2 is unrelated to renin release and that angiotensin II is unlikely to stimulate endogenous prostacyclin biosynthesis under these conditions in man.

The ability to 4-hydroxylate debrisoquine is related to recurrence of bladder cancer.

Oxidative metabolism by cytochrome P450 enzymes is often involved in the activation of environmental procarcinogens. Debrisoquine, mephenytoin, and dapsone were used as in vivo probes for the activities of P4502D6, 2CMP, and 3A4, respectively, as well as dapsone for N-acetyltransferase, in order to assess the relationship between such activities and the relative risk of recurrence of bladder cancer. Urinary recovery ratios of debrisoquine and dapsone and the R/S ratio of mephenytoin were measured in an 0-8 h urine sample after simultaneous administration of debrisoquine (10 mg) and racemic mephenytoin (100 mg), and the administration of dapsone (100 mg) one week later, to patients undergoing local surgical resection of transitional cell bladder cancer of G-I, G-II, or G-III histopathology. In addition, plasma levels of dapsone and mono-acetyldapsone were determined in an 8 h plasma sample to determine the N-acetylation phenotype. Patients were followed for 3 years, to the time of tumour recurrence, or death. Three patients were lost to follow-up; of the remaining 95 patients, 55 had tumour recurrence. The debrisoquine recovery ratio was significantly greater in patients with recurrence than in individuals who remained disease-free. Among the 65 patients with non-aggressive (G-I and G-II) histopathology, two patients were lost to follow-up and 32 had tumour recurrence. In this subgroup, the debrisoquine recovery ratio was again found to be significantly greater in those individuals with tumour recurrence (p < 0.003).(ABSTRACT TRUNCATED AT 250 WORDS)

Low activity of dapsone N-hydroxylation as a susceptibility risk factor in aggressive bladder cancer.

N-arylamines involved in the pathogenesis of bladder cancer, require metabolic activation via N-hydroxylation. The efficiency of in vivo N-hydroxylation of dapsone, a non-carcinogenic arylamine, may, therefore, provide a host susceptibility measure of risk of developing bladder cancer. To investigate this possibility, the dapsone recovery ratio, a phenotypic measure of the efficiency of dapsone hydroxylation, has been measured in a case control study in an urban UK population, comparing patients with aggressive bladder cancer (n = 33), non-aggressive bladder cancer (n = 60) and controls (n = 108). Dapsone recovery ratio in controls exhibited a unimodal distribution. Patients with aggressive bladder cancer had a similar distribution but significantly lower mean value (p < 0.005). Logistic regression analysis, controlling for sex, age, smoking habit and alcohol consumption confirmed a significant (p < 0.05) association between the dapsone recovery ratio and aggressive bladder cancer. Subjects in the lowest tertile of dapsone recovery ratio had a relative risk to 5.4-fold greater than subjects in the upper tertile (p < 0.009), and a trends test was significant (p < 0.001). There was no significant association between dapsone recovery ratio and non-aggressive bladder cancer. These results do not support the hypothesis that the drug metabolizing enzymes involved in dapsone N-hydroxylation are involved in causing bladder cancer. Instead, they suggest the opposite, the observation that low enzyme activity was associated with increased risk is consistent with this enzyme providing a detoxification mechanism for environmental procarcinogens.

The procarcinogen hypothesis for bladder cancer: activities of individual drug metabolizing enzymes as risk factors.

Bladder cancer provides the most definitive example for an association between environmental agents and cancer. However, in the absence of industrial occupational exposure, the primary carcinogen is rarely identified, and the mechanisms involved in cancer formation are poorly understood. The environmental procarcinogen hypothesis of tumour pathogenesis proposes that many carcinogens require metabolic activation by drug metabolizing enzymes to form the proximate carcinogen. A balance of exposure to the carcinogen, the activity of the enzymes involved in either formation of proximate carcinogen, or production of non-toxic metabolites, will determine tumour risk. We have used mephenytoin, debrisoquine and dapsone as selective probes for the phenotypic measures of activity of CYP2C19, CYP2D6, and CYP3A4, respectively. Within subject reproducibility of phenotypic measures, and the lack of cross-inhibition when the three drugs are given in a concurrent cocktail, have been confirmed. We have applied the cocktail drug approach in two, non-overlapping series of cases with bladder cancer and matched controls. In both series, patients with aggressive bladder cancer (GIII histopathology) had a history of excess alcohol intake, an under-representation of poor metabolizers of debrisoquine, a significant mean reduction in dapsone recovery ratio, but no difference in mephenytoin phenotype. Collectively, these observations involving multiple routes of drug metabolism support the procarcinogen environmental hypothesis for bladder cancer and suggest that measurement of activity of selected individual drug metabolizing enzymes involved in the pathogenesis of this tumour can be used to identify subjects at high risk of developing bladder cancer.

Stereoselective mephobarbital hydroxylation cosegregates with mephenytoin hydroxylation.

The 8-hour urinary recovery of 4-hydroxy-mephobarbital has been measured after oral administration of racemic mephobarbital (90 mg) in 17 extensive (EM) and six poor (PM) metabolizer phenotypes of mephenytoin. The recovery of this metabolite was measurable in every EM and ranged from 2.5% to 48% (10.9% +/- 1.9% of dose), but was not detected in any PM (less than 1% of dose). In EMs, the 8-hour urine recovery of 4-OH-mephobarbital after mephobarbital was approximately half that of 4-OH-mephenytoin over the same time after mephenytoin administration. One EM received similar doses of R- and S-mephobarbital on separate occasions. Urinary recovery of 4-OH-mephobarbital was 33% and less than 1%, respectively. These results suggest that mephobarbital is stereoselectively hydroxylated by the same drug metabolizing enzyme that is responsible for the stereoselective aromatic hydroxylation of mephenytoin.

Pharmacokinetics and pharmacodynamics of ethanol, whiskey, and ethanol with n-propyl, n-butyl, and iso-amyl alcohols.

Plasma ethanol concentration, reaction time, and electroencephalogram (EEG) were recorded in 6 normal men after ingestion of ethanol along (Group 1), whiskey (Group 2), or a mixture of ethanol, n-propanol, n-butanol, and iso-amyl alcohol (Group 3). The peak plasma ethanol concentration and the total area under the plasma concentration:time curve of ethanol did not depend upon the type of drink given, but the half-life of the terminal exponential phase of ethanol elimination was longer in Group 3. In each study period reaction time increased, there was a relative increase in delta activity (2 to 3 Hz) and a fall in mean dominant frequency in EEG activity. The extent of increase in reaction time depended on the rate of increase in plasma ethanol concentration and correlated with the concentration of ethanol while the plasma concentration of ethanol was falling. Differences in the effects of ethanol between study periods were minimal.

Effects of an oral contraceptive on hepatic size and antipyrine metabolism in premenopausal women.

Liver volume and antipyrine disposition have been investigated in healthy premenopausal women who received 30 microgram ethinyl oestradiol + 500 microgram dl-norgesterol as an oral contraceptive. Six months' treatment was associated with a 17% increase in liver volume while no change occurred in age-matched control subjects. In the same subjects the contraceptive decreased antipyrine clearance by 21%. Thus the contraceptive markedly reduced drug-metabolizing activity per unit volume of liver by 33%. In additional subjects, discontinuation of the contraceptive resulted in a 30% increase in antipyrine clearance. These observations confirm that conventional oral contraceptive therapy to premenopausal women increases hepatic size and that it is a potent inhibitor of drug-metabolizing activity.

A pharmacodynamic interaction between caffeine and phenylpropanolamine.

The pharmacokinetic and pharmacodynamic interaction between caffeine and phenylpropanolamine has been investigated in six normal subjects in a double-blind, placebo-controlled, Latin-square design study. After 3 days on a 100 mEq sodium, xanthine-free diet, fasting subjects were placed in a supine position and were given 25 mg phenylpropanolamine and placebo, 250 mg caffeine and placebo, or 25 mg phenylpropanolamine and 250 mg caffeine in random order. Blood pressure, pulse, plasma renin activity, and plasma catecholamine levels were measured before and for 3 hours after drug administration. Plasma and urinary phenylpropanolamine, caffeine, and caffeine metabolite levels were measured serially for 48 hours. Coadministration of caffeine and phenylpropanolamine produced an additive increase in blood pressure. This effect could not be explained by any pharmacokinetic interaction between the two drugs and occurred even though phenylpropanolamine attenuated the epinephrine and renin response to caffeine. These data suggest that a clinically relevant interaction between caffeine and phenylpropanolamine does occur in drug-free subjects and that this interaction cannot be explained by a mechanism involving the sympathetic or renin-angiotensin systems.

Influence of probenecid and spironolactone on furosemide kinetics and dynamics in man.

The pharmacokinetics and pharmacodynamics following administration of furosemide (40 mg intravenously) have been studied before and after treatment with probenecid (0.5 gm orally every 6 hr for 3 days) and spironolactone (200-mg initial oral dose followed by 50 mg every 6 hr for 3 days) in 6 normal male subjects. Urine losses during each study period were replaced with saline-dextrose-KCl intravenously. The study was performed with the use of a Latin-square design. Probenecid pretreatment induced significant reductions in renal clearance of furosemide by 78%, the extrarenal clearance by 56%, and the volume of distribution by 52%. As a consequence, furosemide half-life was increased by 54%. Probenecid significantly reduced the rate of sodium excretion at all plasma concentrations of furosemide, but the ratio between urinary furosemide concentration and urinary sodium concentration was not altered. Since the proportion of furosemide excreted unchanged in the urine was not markedly changed, total diuretic response was not influenced by probenecid. There was no evidence of any pharmacokinetic interaction between spironolactone and furosemide. The relationship of furosemide kinetics to dynamics observed in these studies confirms that, in man, the diuretic response is determined by drug that reaches the renal tubule rather than the drug level in plasma.